Translational analysis of combination of 5-fluorouracil (FU), interferon (IFN)-alpha2, and nivolumab in unresectable fibrolamellar liver cancer.
Authors: Sunyoung S. Lee, Fei Duan, Shadi Chamseddine, Sonali Jindal, Sreyashi Basu, Shalini Yadav, James Allison, Padmanee Sharma, Yehia I. Abugabal, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2023)

e16198 Background: Fibrolamellar liver cancer (FLC) is a rare malignancy and involves multidisciplinary approaches including surgery, liver-directed, and systemic treatment. Combination of 5-fluorouracil (FU) and interferon (IFN)-a2 has long been used for FLC. We had a hypothesis that addition of anti-PD1 to 5FU+IFN-a2 may further improve clinical outcome and modulation of FLC tumor microenvironment. Methods: We treated 3 patients with 5FU+IFN-a2+nivolumab (N): 5FU 200 mg/m2 7-day-on/7-day-off and IFN-a2 (4 million U/m2 3 times/week while on 5-FU) for 8 weeks, followed by on-treatment biopsy and addition of N 480 mg every 4 weeks to 5FU+IFN-a2. Those who had conversion of unresectable disease to resectable one had the resected tumors analyzed. Gene expression profiling and immunohistochemistry (IHC) staining of immune cells were performed to investigate the evolution of tumor microenvironment on treatment. Results: 26 and 29 year-old patients had unresectable FLC with a 6.1 cm tumor in seg IV liver invading the common hepatic duct, and a 19.5 cm tumor, metastatic peritoneal nodules, and abdominal lymphadenopathy, respectively. After 9 and 5 months of therapy, unresectable tumors were converted to resectable ones with partial response (PR): the former had left hepatectomy and bile duct resection; the latter, left hepatectomy, resection of the omentum, spleen, left diaphragm, and lymph node dissection. A 20 year-old patient had multifocal liver tumors with peritoneal carcinomatosis and lymph nodes. He received treatment for 5 months and achieved stable disease, but hepatic tumor bleeding led to treatment discontinuation. 2 patients with PR had increased expression of genes related to T cells, CD8+T cells, Th1 cells, NK cells, cytotoxic cells, macrophages, dendritic cells, neutrophils, and B cells, subsequently on tumors before-treatment, on-treatment (5FU+IFN-a2), post-surgery (5FU+IFN-a2+N). IHC staining confirmed an increase in CD8+T cell infiltration after treatment with 5FU+IFN-a2 and 5FU+IFN-a2+N. The third patient whose disease was not converted to a resectable disease showed a decrease in genes related to Th1 cells, cytotoxic cells, dendritic cells, and neutrophils on-treatment biopsy (5FU+IFN-a2). This patient had a marginal increase in CD8+T cell infiltration on exposure to 5FU+IFN-a2. Conclusions: This clinical outcome of converting unresectable disease to resectable one suggests synergy of 5FU+IFN-a2 combined with N. The robust increased expression of genes related to immune system activation and increased infiltration of CD8+T cells on 5FU+IFN-a2+N may explain this clinical efficacy. Pro-inflammatory evolution of tumors on treatment could be used as predictive biomarkers. More prospective data are indicated to further confirm our hypothesis. Clinical trial information: NCT04380545 .